The overall goal of this Laboratory Program is to discover anti-cancer lead compounds from marine cyanobacteria using mechanism-based screening strategies. An underlying hypothesis of this screening strategy is that it will generate agents active to the major solid tumors (lung, colon, breast, prostate) which are not effectively treated at present. Marine cyanobacteria are abundant as both free-living and symbiotic tropical organisms, and have a correspondingly rich and diverse secondary metabolism. The specific aims of this work are to: 1) to produce 1000 extracts from field collected and cultured tropical marine microalgae, mainly cyanobacteria. New cultures of marine cyanobacteria are to come from field isolates with a focus on those of low natural biomass or found in symbiosis with marine invertebrates, such as sponges and tunicates; 2) to characterize cyanobacterial strains that possess exceptional capacities for natural products synthesis at the morphological, culture and molecular level, and to use these data to enhance the collection and culture paradigm of additional cyanobacteria for anti-cancer drug screening; 3) to promote reduce-complexity fractions of these extracts by a medium throughput sold-phase chromatographic strategy; 4) to evaluate these reduced complexity fraction, approximately 8,000 total, in innovative mechanism- based anti-cancer assays available at the Novartis Institute for Biomedical Research; 5) to rapidly HPLC-purify compounds from reduced complexitgy fractions to obtain pure natural products and assay these in the relevant mechanism-based assays; 6) to elucidate the structures of pure and active compounds employing efficient and modern spectroscopic methods, emphasizing newly developed pulsed field gradient 2D NMR techniques; 7) to scale-up the culture of re-collect active species to provide samples for pharmacological and clinical investigation; 8) to produce semi- synthetic analogs of active compounds for exploration of structure-activity relationships in new lead compounds 9) to obtain patent coverage on promising anti-tumor natural products and their derivatives.